The Slug transcription factor modulates the complete or partial conversion of sessile epithelial cells into migrating fibroblast-like cells during embryonic development, wound healing, and carcinogenesis. During the course of our studies examining the role of Slug in ultraviolet radiation (UVR)-induced skin tumor progression, we made the unexpected observation that Slug knock- out (KO) mice are resistant to the acute inflammatory effects of UVR on the skin: edema, erythema, neutrophil influx, and epidermal necrosis. Our preliminary studies indicate that a major defect in the acute UVR response of Slug knockout mice is failure of neutrophil recruitment into the skin and suggest that the defect lies in altered release of proinflammatory mediators from UVR-exposed knockout keratinocytes rather than in defects in dermal mast cell or circulating neutrophil number or function. To distinguish the role of Slug in the epidermis from its role in the neutrophil, we will construct bone marrow chimeric and conditional KO mice that lack Slug activity in the epidermis but have wild type (WT) hematopoietic cells and determine if their cutaneous inflammatory response to UVR exposure differs from that of mice with WT epidermis. Production of inflammatory modulators by epidermal keratinocytes will be assessed using microarrays to determine if there is aberrant production of proinflammatory mediators by UVR- exposed Slug KO keratinocytes. The ability of Slug KO neutrophils to migrate in response to chemotactic signals will be assayed in vitro to identify possible deficits in adhesion and migration of these cells. Our studies will provide insight into the identity of genes under transcriptional control of Slug that are key to a robust local inflammatory response. This represents the first investigation of a novel role for the Slug transcription factor in modulating the acute inflammatory response. Slug may represent a new target for therapeutic control of acute inflammation, and the present studies will provide the foundation for more detailed investigations of this possibility. PUBLIC HEALTH RELEVANCE: Sunlight induces both acute skin damage (sunburn) and long term skin damage (skin cancer). The role of the Slug transcription factor in promoting skin cancer development has been documented, and we have preliminary data suggesting an unexpected but important role for Slug in modulating sunburn. These studies will investigate the mechanism by which Slug controls the inflammation associated with sunburn;this may identify Slug as a target for prevention and treatment of both sunburn and, ultimately, skin cancer.